Metabolic Reprogramming toward Aerobic Glycolysis and the Gut Microbiota Involved in the Brain Amyloid Pathology

SIMPLE SUMMARY: Amyloid-β toxicity is attributed to oligomer and fibrillar amyloid-β, which either damages the neurons or initiates an intracellular signaling cascade toward neuronal cell death. In addition to the amyloid-β aggregation, an emerging hallmark of Alzheimer’s disease is the metabolic reprogramming toward aerobic glycolysis. This article describes the emerging features of Alzheimer’s disease from the aspect of alternation in the central metabolic pathways in the human brain. The potential practical approaches for therapeutic intervention for the improvement of metabolic disorders are also described. The dietary intervention such as the use of ketone-mediated nutritional therapeutics is a promising strategy for complementing the brain energy levels in patients with Alzheimer’s disease as a high-ketogenic diet may restore the metabolic imbalance caused by aerobic glycolysis in the neurons and microglia. ABSTRACT: Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of metabolic reprogramming in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method for the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in the near future.